HIF-2α downregulation in the absence of functional VHL is not sufficient for renal cell differentiation

Michael D. Hughes, Erilda Kapllani, Ashlynn E. Alexander, Robert D. Burk, Alan R. Schoenfeld

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary as well as sporadic clear cell renal carcinomas. The product of the VHL gene, pVHL, acts to target hypoxia-inducible factor alpha (HIF-α) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2α in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2α toward cellular pVHL activities. Results: Knockdown of HIF-2α resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2α regulation. However, cellular morphological changes and downregulation of integrins α5 and β1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2α reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2α knockdown cells, indicating that these pVHL functions may occur independently of HIF-2α downregulation. Conclusion: These results indicate that HIF-2α regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2α dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis.

Original languageEnglish (US)
Article number13
JournalCancer Cell International
Volume7
DOIs
StatePublished - Jun 28 2007

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Cell Differentiation
Down-Regulation
Kidney
Ubiquitination
Differentiation Antigens
RNA Interference
Cell Cycle Checkpoints
Tumor Suppressor Genes
Fibronectins
Renal Cell Carcinoma
Integrins
Carcinogenesis
Collagen
Cell Line
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HIF-2α downregulation in the absence of functional VHL is not sufficient for renal cell differentiation. / Hughes, Michael D.; Kapllani, Erilda; Alexander, Ashlynn E.; Burk, Robert D.; Schoenfeld, Alan R.

In: Cancer Cell International, Vol. 7, 13, 28.06.2007.

Research output: Contribution to journalArticle

Hughes, Michael D. ; Kapllani, Erilda ; Alexander, Ashlynn E. ; Burk, Robert D. ; Schoenfeld, Alan R. / HIF-2α downregulation in the absence of functional VHL is not sufficient for renal cell differentiation. In: Cancer Cell International. 2007 ; Vol. 7.
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AU - Schoenfeld, Alan R.

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AB - Background: Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary as well as sporadic clear cell renal carcinomas. The product of the VHL gene, pVHL, acts to target hypoxia-inducible factor alpha (HIF-α) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2α in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2α toward cellular pVHL activities. Results: Knockdown of HIF-2α resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2α regulation. However, cellular morphological changes and downregulation of integrins α5 and β1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2α reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2α knockdown cells, indicating that these pVHL functions may occur independently of HIF-2α downregulation. Conclusion: These results indicate that HIF-2α regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2α dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis.

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